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1.  Peroxisome Proliferator Activated Receptor Ligands as Regulators of Airway Inflammation and Remodelling in Chronic Lung Disease 
PPAR Research  2007;2007:14983.
Inflammation is a major component in the pathology of chronic lung diseases, including asthma. Anti-inflammatory treatment with corticosteroids is not effective in all patients. Thus, new therapeutic options are required to control diverse cellular functions that are currently not optimally targeted by these drugs in order to inhibit inflammation and its sequelae in lung disease. Peroxisome proliferator activated receptors (PPARs), originally characterised as regulators of lipid and glucose metabolism, offer marked potential in this respect. PPARs are expressed in both lung infiltrating and resident immune and inflammatory cells, as well as in resident and structural cells in the lungs, and play critical roles in the regulation of airway inflammation. In vitro, endogenous and synthetic ligands for PPARs regulate expression and release of proinflammatory cytokines and chemoattractants, and cell proliferation and survival. In murine models of allergen-induced inflammation, PPARα and PPARγ ligands reduce the influx of inflammatory cells, cytokine and mucus production, collagen deposition, and airways hyperresponsiveness. The activity profiles of PPAR ligands differ to corticosteroids, supporting the hypothesis that PPARs comprise additional therapeutic targets to mimimise the contribution of inflammation to airway remodelling and dysfunction.
doi:10.1155/2007/14983
PMCID: PMC2065911  PMID: 18000530
2.  PPAR-γ regulates inflammation and renin-angiotensin system activity in hypothalamic paraventricular nucleus and ameliorates peripheral manifestations of heart failure 
Hypertension  2011;59(2):477-484.
Activation of peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, has been shown to inhibit the production of proinflammatory cytokines and, in peripheral tissues, to down-regulate the renin-angiotensin system (RAS). PPAR-γ is expressed in key brain areas involved in cardiovascular and autonomic regulation. We hypothesized that activation of central PPAR-γ would reduce sympathetic excitation and ameliorate peripheral manifestations of heart failure (HF) by inhibiting central inflammation and brain RAS activity. Two weeks after coronary artery ligation, HF rats received an intracerebroventricular (ICV) infusion of the PPAR-γ agonist pioglitazone or vehicle for another 2 weeks. PPAR- expression in the paraventricular nucleus of hypothalamus (PVN), an important cardiovascular region, was unchanged in HF compared with sham-operated (SHAM) rats. However, PPAR-γ DNA binding activity was reduced, nuclear factor-kB activity was increased, and expression of proinflammatory cytokines and angiotensin II type-1 receptor was augmented in the HF rats. Mean blood pressure response to ganglionic blockade was greater, plasma norepinephrine levels, lung/body weight, right ventricle/body weight, and left ventricular end-diastolic pressure were increased and maximal left ventricular dP/dt was decreased. All these findings were ameliorated in HF rats treated with ICV pioglitazone, which increased PPAR-γ expression and DNA binding activity in PVN. The results demonstrate that cardiovascular and autonomic mechanisms leading to heart failure after myocardial infarction can be modulated by activation of PPAR-γ in the brain. Central PPAR-γ may be a novel target for treatment of sympathetic excitation in myocardial infarction-induced HF.
doi:10.1161/HYPERTENSIONAHA.111.182345
PMCID: PMC3266457  PMID: 22083161
peroxisome proliferator-activated receptor-γ; proinflammatory cytokines; renin-angiotensin system; nuclear factor-kB; autonomic regulation
3.  Role of Peroxisome Proliferator-Activated Receptor-γ in Vascular Inflammation 
Vascular inflammation plays a crucial role in atherosclerosis, and its regulation is important to prevent cerebrovascular and coronary artery disease. The inflammatory process in atherogenesis involves a variety of immune cells including monocytes/macrophages, lymphocytes, dendritic cells, and neutrophils, which all express peroxisome proliferator-activated receptor-γ (PPAR-γ). PPAR-γ is a nuclear receptor and transcription factor in the steroid superfamily and is known to be a key regulator of adipocyte differentiation. Increasing evidence from mainly experimental studies has demonstrated that PPAR-γ activation by endogenous and synthetic ligands is involved in lipid metabolism and anti-inflammatory activity. In addition, recent clinical studies have shown a beneficial effect of thiazolidinediones, synthetic PPAR-γ ligands, on cardiovascular disease beyond glycemic control. These results suggest that PPAR-γ activation is an important regulator in vascular inflammation and is expected to be a therapeutic target in the treatment of atherosclerotic complications. This paper reviews the recent findings of PPAR-γ involvement in vascular inflammation and the therapeutic potential of regulating the immune system in atherosclerosis.
doi:10.1155/2012/508416
PMCID: PMC3409528  PMID: 22888436
4.  The importance of leukotrienes in airway inflammation in a mouse model of asthma 
The Journal of Experimental Medicine  1996;184(4):1483-1494.
Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5- lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.
PMCID: PMC2192843  PMID: 8879219
5.  PPAR-alpha in cutaneous inflammation 
Dermato-endocrinology  2011;3(1):23-26.
Peroxisome proliferator-activated receptor (PPAR)-alpha is a fatty acid activated transcription factors that belongs to the nuclear hormone receptor family. Primarily PPAR-alpha serves as a lipid sensor. While PPAR-alpha controls enzymes from the lipid and glucose metabolism in the liver, heart and muscles, PPAR-alpha is also involved in skin homeostasis. PPAR-alpha controls keratinocyte proliferation/differentiation, contributes to wound healing and regulates skin inflammation. PPAR-alpha activation exerts anti-inflammatory effects in various skin conditions such as irritant and allergic contact dermatitis, atopic dermatitis and UV-induced erythema, rendering investigations into the functions of PPAR-alpha necessary to provide better understandings to treat many inflammatory skin disorders.
doi:10.4161/derm.3.1.14615
PMCID: PMC3051849  PMID: 21519405
PPAR; allergic contact dermatitis; atopic dermatitis; psoriasis; skin barrier
6.  Peroxisome proliferator-activated receptors (PPARs) in dermatology 
Dermato-endocrinology  2011;3(3):130-135.
Since their discovery it has become clear that peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the genetic regulation of the lipid metabolism and energy homoeostasis. Subsequently, accumulating evidence suggests a role of PPARs in genomic pathways including the regulation of cell growth, apoptosis and differentiation. These findings indicate that PPARs and PPAR agonists play an important role in inflammatory responses and tumor promotion. Because of their diverse biologic activities on keratinocytes and other skin cells, PPARs represent a major research target for the understanding and treatment of many skin pathologies, such as hyperproliferative and inflammatory diseases. Overmore recent clinical trials identified PPARs as promising drug targets for the prevention and treatment of various diseases in the field of dermatology. The present review summarizes the current knowledge of PPAR functions in various skin disorders particularly those involving inflammation and epidermal hyperproliferation (i.e., psoriasis, atopic dermatitis, acne, scleroderma, skin malignancies).
doi:10.4161/derm.3.3.15025
PMCID: PMC3219163  PMID: 22110772
PPAR; dermatology; inflammation; atopic dermatitis; psoriasis; scleroderma; cancer
7.  The Role of PPAR Ligands in Controlling Growth-Related Gene Expression and their Interaction with Lipoperoxidation Products 
PPAR Research  2008;2008:524671.
Peroxisome proliferators-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The three PPAR isoforms (α, γ and β/δ) have been found to play a pleiotropic role in cell fat metabolism. Furthermore, in recent years, evidence has been found regarding the antiproliferative, proapoptotic, and differentiation-promoting activities displayed by PPAR ligands, particularly by PPARγ ligands. PPAR ligands affect the expression of different growth-related genes through both PPAR-dependent and PPAR-independent mechanisms. Moreover, an interaction between PPAR ligands and other molecules which strengthen the effects of PPAR ligands has been described. Here we review the action of PPAR on the control of gene expression with particular regard to the effect of PPAR ligands on the expression of genes involved in the regulation of cell-cycle, differentiation, and apoptosis. Moreover, the interaction between PPAR ligands and 4-hydroxynonenal (HNE), the major product of the lipid peroxidation, has been reviewed.
doi:10.1155/2008/524671
PMCID: PMC2443425  PMID: 18615196
8.  Constitutive Activation of Smad Signaling and Up-regulation of Smad-Dependent Collagen Gene Expression in Mouse Embryonic Fibroblasts Lacking PPAR-γ:Possible Link with Fibrosis 
Transforming growth factor-β (TGF-β), a potent inducer of collagen synthesis, is implicated in fibrosis. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor that regulates adipogenesis and is recognized as a pleiotropic transcription factor. We demonstrated previously that activation of PPAR-γ by natural and pharmacologic ligands abrogated the stimulation of collagen gene expression induced by TGF-β in skin fibroblasts. The goal of this study was to characterize the physiologic role of endogenous PPAR-γ in regulation of TGF-β signaling and collagen gene expression. We found that basal collagen gene expression was markedly elevated in mouse embryonic fibroblasts (MEFs) lacking PPAR-γ and PPAR-γ ligand 15d-PGJ2 failed to reduce the elevated levels of collagen. Reconstitution of PPAR-γ null MEFs with ectopic PPAR-γ resulted in down-regulation of COL1A2 promoter activity. In contrast to control MEFs, PPAR-γ null MEFs displayed elevated expression of Type I TGF-β receptor TβRI, and produced more TGF-β1. Furthermore, PPAR-γ null MEFs showed Smad2 and Smad3 phosphorylation even in the absence of stimulation by exogenous TGF-β. Constitutive Smad2/3 phosphorylation in PPAR-γ null MEFs was associated with ligand-independent interaction of Smad3 with its cognate DNA recognition site and with p300, a coactivator previously implicated in mediating TGF-β responses. These results indicate that absence of PPAR-γ in MEFs is associated with constitutive up-regulation of collagen gene expression and Smad activation, at least in part, due to autocrine TGF-β stimulation. Importantly, in scleroderma skin fibroblasts, the levels of PPAR-γ were significantly less compared to healthy controls. Therefore, endogenous PPAR-γ may have a physiologic role in controlling Smad-dependent Type I collagen gene expression in fibroblasts and in tissue homeostasis.
doi:10.1016/j.bbrc.2008.07.014
PMCID: PMC3157939  PMID: 18627765
9.  15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats 
Journal of Clinical Investigation  2000;106(2):189-197.
Peroxisome proliferator–activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have a dominant regulatory role in adipocyte and monocyte differentiation. PPAR-γ agonists are also negative regulators of macrophage activation and have modulatory effects on tumorigenesis. In this study we demonstrate that synovial tissue localized expression of PPAR-γ in patients with rheumatoid arthritis (RA). We detected markedly enhanced expression of PPAR-γ in macrophages, as well as modestly enhanced expression in the synovial lining layer, fibroblasts, and endothelial cells. Activation of the PPAR-γ by 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and the synthetic PPAR-γ ligand (troglitazone) induced RA synoviocyte apoptosis in vitro. Moreover, intraperitoneal administration of these PPAR-γ ligands ameliorated adjuvant-induced arthritis with suppression of pannus formation and mononuclear cell infiltration in female Lewis rats. Anti-inflammatory effects of 15d-PGJ2 were more potent than troglitazone. These findings suggest that PPAR-γ may be an important immunoinflammatory mediator and its ligands, especially 15d-PGJ2, may be useful in the treatment of RA.
PMCID: PMC314310  PMID: 10903334
10.  Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. 
Journal of Clinical Investigation  1997;100(12):3083-3092.
Immunized mice after inhalation of specific antigen have the following characteristic features of human asthma: airway eosinophilia, mucus and Th2 cytokine release, and hyperresponsiveness to methacholine. A model of late-phase allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil is the key effector cell of allergen-induced pulmonary inflammation and hyperresponsiveness.
PMCID: PMC508521  PMID: 9399955
11.  PPARs in Calorie Restricted and Genetically Long-Lived Mice 
PPAR Research  2006;2007:28436.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptors superfamily. The three subtypes, PPARα, PPARγ, and PPARβ/δ, are expressed in multiple organs. These transcription factors regulate different physiological functions such as energy metabolism (including lipid and carbohydrate metabolism), insulin action, and immunity and inflammation, and apparently also act as important mediators of longevity and aging. Calorie restriction (CR) is the most effective intervention known to delay aging and increase lifespan. Calorie restriction affects the same physiological functions as PPARs. This review summarizes recent findings on the effects of CR and aging on the expression of PPARγ, α, and β/δ in mice and discusses possible involvement of PPARs in mediating the effects of murine longevity genes. The levels of PPARs change with age and CR appears to prevent these alterations which make “PPARs-CR-AGING” dependence of considerable interest.
doi:10.1155/2007/28436
PMCID: PMC1779582  PMID: 17389764
12.  Multiple Interactions between Peroxisome Proliferators-Activated Receptors and the Ubiquitin-Proteasome System and Implications for Cancer Pathogenesis 
PPAR Research  2008;2008:195065.
The peroxisome proliferator-activated receptors (PPAR) α, β/δ, and γ are ligand-activated nuclear receptors involved in a number of physiological processes, including lipid and glucose homeostasis, inflammation, cell growth, differentiation, and death. PPAR agonists are used in the treatment of human diseases, like type 2 diabetes and dyslipidemia, and PPARs appear as promising therapeutic targets in other conditions, including cancer. A better understanding of the functions and regulation of PPARs in normal and pathological processes is of primary importance to devise appropriate therapeutic strategies. The ubiquitin-proteasome system (UPS) plays an important role in controlling level and activity of many nuclear receptors and transcription factors. PPARs are subjected to UPS-dependent regulation. Interestingly, the three PPAR isotypes are differentially regulated by the UPS in response to ligand-dependent activation, a phenomenon that may be intrinsically connected to their distinct cellular functions and behaviors. In addition to their effects ongene expression, PPARs appear to affect protein levels and downstream pathways also by modulating the activity of the UPS in target-specific manners. Here we review the current knowledge of the interactions between the UPS and PPARs in light of the potential implications for their effects on cell fate and tumorigenesis.
doi:10.1155/2008/195065
PMCID: PMC2423003  PMID: 18551186
13.  THE ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS IN CARCINOGENESIS AND CHEMOPREVENTION 
Nature Reviews. Cancer  2012;12(3):181-195.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a balanced review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.
doi:10.1038/nrc3214
PMCID: PMC3322353  PMID: 22318237
14.  The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases 
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR-β/δ enhances fatty acids metabolism. Thus, PPAR family of nuclear receptors plays a major regulatory role in energy homeostasis and metabolic function. The present review critically analyzes the protective and detrimental effect of PPAR agonists in dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity.
doi:10.4103/2231-4040.90879
PMCID: PMC3255347  PMID: 22247890
Diabetes; dyslipidemia; peroxisome proliferator-activated receptors
15.  PPARs Mediate Lipid Signaling in Inflammation and Cancer 
PPAR Research  2008;2008:134059.
Lipid mediators can trigger physiological responses by activating nuclear hormone receptors, such as the peroxisome proliferator-activated receptors (PPARs). PPARs, in turn, control the expression of networks of genes encoding proteins involved in all aspects of lipid metabolism. In addition, PPARs are tumor growth modifiers, via the regulation of cancer cell apoptosis, proliferation, and differentiation, and through their action on the tumor cell environment, namely, angiogenesis, inflammation, and immune cell functions. Epidemiological studies have established that tumor progression may be exacerbated by chronic inflammation. Here, we describe the production of the lipids that act as activators of PPARs, and we review the roles of these receptors in inflammation and cancer. Finally, we consider emerging strategies for therapeutic intervention.
doi:10.1155/2008/134059
PMCID: PMC2606065  PMID: 19125181
16.  Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination 
Background
Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS). Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-γ (IFN-γ) and lipopolysaccharide (LPS). Peroxisome proliferator-associated receptor (PPAR) pathways are involved in the control of the inflammatory processes, and PPAR-β seems to play an important role in the regulation of central inflammation. In addition, PPAR-β agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-β agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-γ and LPS.
Methods
Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-γ and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG). The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), inducible NO synthase (i-NOS), PPAR-β, PPAR-γ, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and high molecular weight neurofilament protein (NF-H). GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4) and ED1 labeling.
Results
GW 501516 decreased the IFN-γ-induced up-regulation of TNF-α and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-β agonist. However, it increased IL-6 m-RNA expression. In demyelinating cultures, reactivity of both microglial cells and astrocytes was observed, while the expression of the inflammatory cytokines and iNOS remained unaffected. Furthermore, GW 501516 did not protect against the demyelination-induced changes in gene expression.
Conclusion
Although GW 501516 showed anti-inflammatory activity, it did not protect against antibody-mediated demyelination. This suggests that the protective effects of PPAR-β agonists observed in vivo can be attributed to their anti-inflammatory properties rather than to a direct protective or trophic effect on oligodendrocytes.
doi:10.1186/1742-2094-6-15
PMCID: PMC2687435  PMID: 19422681
17.  Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders 
PPAR Research  2008;2008:679137.
Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α, γ, and σ) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.
doi:10.1155/2008/679137
PMCID: PMC2430035  PMID: 18566691
18.  Peroxisome Proliferator-Activated Receptors and Acute Lung Injury 
PPAR Research  2007;2007:63745.
Peroxisome proliferator-activated receptors are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARs regulate several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid biosynthesis and glucose metabolism. Recently, PPARs and their respective ligands have been implicated as regulators of cellular inflammatory and immune responses. These molecules are thought to exert anti-inflammatory effects by negatively regulating the expression of proinflammatory genes. Several studies have demonstrated that PPAR ligands possess anti-inflammatory properties and that these properties may prove helpful in the treatment of inflammatory diseases of the lung. This review will outline the anti-inflammatory effects of PPARs and PPAR ligands and discuss their potential therapeutic effects in animal models of inflammatory lung disease.
doi:10.1155/2007/63745
PMCID: PMC1940050  PMID: 17710233
19.  PPARγ as a Potential Target to Treat Airway Mucus Hypersecretion in Chronic Airway Inflammatory Diseases 
PPAR Research  2012;2012:256874.
Airway mucus hypersecretion (AMH) is a key pathophysiological feature of chronic airway inflammatory diseases such as bronchial asthma, cystic fibrosis, and chronic obstructive pulmonary disease. AMH contributes to the pathogenesis of chronic airway inflammatory diseases, and it is associated with reduced lung function and high rates of hospitalization and mortality. It has been suggested that AMH should be a target in the treatment of chronic airway inflammatory diseases. Recent evidence suggests that a key regulator of airway inflammation, hyperresponsiveness, and remodeling is peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor that regulates adipocyte differentiation and lipid metabolism. PPARγ is expressed in structural, immune, and inflammatory cells in the lung. PPARγ is involved in mucin production, and PPARγ agonists can inhibit mucin synthesis both in vitro and in vivo. These findings suggest that PPARγ is a novel target in the treatment of AMH and that further work on this transcription factor may lead to new therapies for chronic airway inflammatory diseases.
doi:10.1155/2012/256874
PMCID: PMC3385647  PMID: 22761606
20.  The Role of Peroxisome Proliferator-Activated Receptors in Colorectal Cancer 
PPAR Research  2012;2012:876418.
Colorectal cancer is one of the most common cancers in the world. Dietary fat intake is a major risk factor for colorectal cancer. Some nuclear hormone receptors play an important role in regulating nutrient metabolism and energy homeostasis. Among these receptors, special attention has been focused on the role of peroxisome proliferator-activated receptors (PPARs) in colorectal cancer, because PPARs are involved in regulation of lipid and carbohydrate metabolism. PPARs are ligand-activated intracellular transcription factors. The PPAR subfamily consists of three subtypes encoded by distinct genes named PPARα, PPARβ/δ, and PPARγ. PPARγ is the most extensively studied subtype of PPARs. Even though many investigators have studied the expression and clinical implications of PPARs in colorectal cancer, there are still many controversies about the role of PPARs in colorectal cancer. In this paper, the recent progresses in understanding the role of PPARs in colorectal cancer are summarized.
doi:10.1155/2012/876418
PMCID: PMC3447370  PMID: 23024650
21.  The PPAR-Platelet Connection: Modulators of Inflammation and Potential Cardiovascular Effects 
PPAR Research  2007;2008:328172.
Historically, platelets were viewed as simple anucleate cells responsible for initiating thrombosis and maintaining hemostasis, but clearly they are also key mediators of inflammation and immune cell activation. An emerging body of evidence links platelet function and thrombosis to vascular inflammation. peroxisome proliferator-activated receptors (PPARs) play a major role in modulating inflammation and, interestingly, PPARs (PPARβ/δ and PPARγ) were recently identified in platelets. Additionally, PPAR agonists attenuate platelet activation; an important discovery for two reasons. First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression. Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade. Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.
doi:10.1155/2008/328172
PMCID: PMC2233896  PMID: 18288284
22.  Peroxisome Proliferator-Activated Receptor-Gamma Expression in the Lung Tissue of Obese Rats 
Yonsei Medical Journal  2011;52(3):495-501.
Purpose
Obesity is a risk factor for asthma and type II diabetes. Peroxisome proliferator-activated receptor (PPAR)-γ has been suggested to regulate inflammatory responses in diabetes and asthma. We investigated whether PPAR-α, PPAR-γ, adiponectin receptors (AdipoR1, AdipoR2), leptin, and tumor necrosis factor (TNF)-α are expressed in rat lung tissues and whether the expression differs between obese Otsuka Long-Evans Tokushima Fatty (OLETF) and lean Long Evans Tokushima Otsuka (LETO) rats.
Materials and Methods
Obese and lean rats were given with a high fat diet or a 30% restricted diet for 32 weeks, and their blood glucose levels and weights were monitored. After 32 weeks, mRNA levels of PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α in lung tissues were measured using real time PCR.
Results
PPAR-α, PPAR-γ, AdipoR1, AdipoR2, leptin, and TNF-α were expressed in both obese and lean rat lung tissues. Increased serum glucose levels on intraperitoneal glucose tolerance testing and a higher weight gain at 32 weeks were observed in OLETF control rats compared to OLETF diet restricted rats. PPAR-γ expression was markedly elevated in obese control and diet restricted rats compared to lean rats, although PPAR-γ expression in obese rats was not affected by diet restriction. Leptin was highly expressed in OLETF rats compared to LETO rats. TNF-α expression was enhanced in OLETF control rats compared LETO diet restricted rats, and decreased by diet restriction. PPAR-α, AdipoR1, and AdipoR2 expression were not significantly different between obese and lean rats.
Conclusion
PPAR-γ was highly expressed in the lung tissues of obese rats and may be a novel treatment target for regulating lung inflammation associated with obesity.
doi:10.3349/ymj.2011.52.3.495
PMCID: PMC3101042  PMID: 21488194
Obesity; peroxisome proliferator activated receptor; adiponectin receptor; lung; leptin; TNF-alpha
23.  Downregulation of peroxisome proliferator-activated receptors (PPARs) in nasal polyposis 
Respiratory Research  2005;6(1):132.
Background
Peroxisome proliferator-activated receptor (PPAR) α, βδ and γ are nuclear receptors activated by fatty acid metabolites. An anti-inflammatory role for these receptors in airway inflammation has been suggested.
Methods
Nasal biopsies were obtained from 10 healthy volunteers and 10 patients with symptomatic allergic rhinitis. Nasal polyps were obtained from 22 patients, before and after 4 weeks of local steroid treatment (fluticasone). Real-time RT-PCR was used for mRNA quantification and immunohistochemistry for protein localization and quantification.
Results
mRNA expression of PPARα, PPARβδ, PPARγ was found in all specimens. No differences in the expression of PPARs were obtained in nasal biopsies from patients with allergic rhinitis and healthy volunteers. Nasal polyps exhibited lower levels of PPARα and PPARγ than normal nasal mucosa and these levels were, for PPARγ, further reduced following steroid treatment. PPARγ immunoreactivity was detected in the epithelium, but also found in smooth muscle of blood vessels, glandular acini and inflammatory cells. Quantitative evaluation of the epithelial immunostaining revealed no differences between nasal biopsies from patients with allergic rhinitis and healthy volunteers. In polyps, the PPARγ immunoreactivity was lower than in nasal mucosa and further decreased after steroid treatment.
Conclusion
The down-regulation of PPARγ, in nasal polyposis but not in turbinates during symptomatic seasonal rhinitis, suggests that PPARγ might be of importance in long standing inflammations.
doi:10.1186/1465-9921-6-132
PMCID: PMC1298337  PMID: 16271155
24.  ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1 
Nature medicine  2011;17(9):1076-1085.
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic × receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.
doi:10.1038/nm.2439
PMCID: PMC3244833  PMID: 21857651
25.  Coactivators in PPAR-Regulated Gene Expression 
PPAR Research  2010;2010:250126.
Peroxisome proliferator-activated receptor (PPAR)α, β (also known as δ), and γ function as sensors for fatty acids and fatty acid derivatives and control important metabolic pathways involved in the maintenance of energy balance. PPARs also regulate other diverse biological processes such as development, differentiation, inflammation, and neoplasia. In the nucleus, PPARs exist as heterodimers with retinoid X receptor-α bound to DNA with corepressor molecules. Upon ligand activation, PPARs undergo conformational changes that facilitate the dissociation of corepressor molecules and invoke a spatiotemporally orchestrated recruitment of transcription cofactors including coactivators and coactivator-associated proteins. While a given nuclear receptor regulates the expression of a prescribed set of target genes, coactivators are likely to influence the functioning of many regulators and thus affect the transcription of many genes. Evidence suggests that some of the coactivators such as PPAR-binding protein (PBP/PPARBP), thyroid hormone receptor-associated protein 220 (TRAP220), and mediator complex subunit 1 (MED1) may exert a broader influence on the functions of several nuclear receptors and their target genes. Investigations into the role of coactivators in the function of PPARs should strengthen our understanding of the complexities of metabolic diseases associated with energy metabolism.
doi:10.1155/2010/250126
PMCID: PMC2929611  PMID: 20814439

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